Human immunodeficiency virus (HIV) infection of the central nervous system (CNS) remains a serious problem due to the persistence of infection, progressive neural degeneration, and resulting cognitive decline. The progression of CNS disease, although slowed by antiretrovirals, is expected to exert an increasingly heavy toll as patients with HIV live longer. The development of therapeutic strategies designed to protect against neuronal damage are needed but have been hindered by a lack of animal models that recapitulate the conditions that lead to neuropathogenesis in HIV infection. Simian immunodeficiency virus infection of macaques is perhaps the best model available but is expensive and restricted by availability of animals. Feline immunodeficiency virus (FIV) offers an alternative model of lentiviral neuropathogenesis which recapitulates all essential aspects of HIV infection in humans. However, the utility of this model has been reduced by its slow CNS disease progression and the absence of behavioral assessment paradigms to track disease progression. We have developed a protocol to increase CNS FIV viral burden in the cats to facilitate CNS disease progression. The objective of this study is to confirm specific behavioral tests that will be used to sensitively and reliably monitor the progression of the disease in these FIV-infected cats. The recent development of versatile feline behavioral testing capabilities by CanCog Technologies has provided the opportunity to design a behavioral test battery sensitive to the cognitive-motor deficits in FIV infected cats. Preliminary observations using a prototype apparatus and video monitoring of activity have indicated that significant behavioral deficits may be detected as early as six months post-inoculation with progressive changes observed at 12 months. It is anticipated that these tests provide sensitive measures of neurological disease progression that can be used to assess the efficacy of therapeutic interventions. The proposed studies will apply behavioral tests to cats infected intracranially with neurotropic FIV and sham-infected matched controls, at 1 week, and 5, 10 and 15 months post-infection. Parallel measures of plasma FIV, CSF FIV and lymphocyte subsets will be taken to provide a comprehensive assessment of each aspect of disease progression, to be compared to behavioral findings. The behavioral data should provide the basic characterization of neurological disease progression needed for the implementation of a feline model suitable for testing of therapeutics. PUBLIC HEALTH RELEVANCE: Feline immunodeficiency virus infection provides an excellent natural model of infection and neuropathogenesis similar to HIV infection in humans. A significant barrier to the use of this model for evaluation of disease mechanisms and testing of new therapeutics is the difficulty of accurately tracking early CNS disease progression. The use and validation of behavioral measures as proposed in this application will provide a sensitive assessment tool capable of quantifying deficits within 1-2 years of infection. Development of the proposed paradigms will greatly facilitate the translation of new therapeutic regimens to a valid in vivo model of HIV neuropathogenesis.